Triphenylene derivatives

ABSTRACT

The present invention relates to compounds of formula (I) ##STR1## wherein Ar is a triphenylene or substituted triphenylene ring system; 
     R 1  is a C 1-3  alkylene moiety; 
     R 2  is hydrogen or a C 1-6  alkyl group; 
     R 3  is a hydroxy C 1-6  alkyl group; 
     R 4  and R 5  are the same or different and are hydrogen, C 1-6  alkyl or hydroxy C 1-6  alkyl, esters thereof derived from condensation of carboxylic acids and hydroxyl groups of R 3 , R 4 , and R 5  ; 
     Acid addition salts thereof, which have been found useful for the treatment of tumors in mammals.

The present invention relates to alkanol derivatives which have beenfound to be inhibitors of tumor growth. More specifically the inventionconcerns aminoalkanol derivatives containing a triphenylene orsubstituted triphenylene ring system, methods for the synthesis thereof,pharmaceutical formulations thereof, and the use thereof as antitumoragents.

There is accordingly provided, in a first aspect, compounds of thegeneral formula (I) ##STR2## wherein Ar is a triphenylene or substitutedtriphenylene ring;

R¹ is a C₁₋₃ alkylene moiety;

R² is hydrogen or a C₁₋₆ alkyl group;

R³ is a hydroxy C₁₋₆ alkyl group;

R⁴ and R⁵ are the same or different and are hydrogen, C₁₋₆ alkyl orhydroxy C₁₋₆ alkyl, esters thereof derived from condensation ofcarboxylic acids and hydroxyl groups of R³,R⁴, and R⁵ ;

Acid addition salts thereof.

The side chain (i.e. as --R¹ --NR² CR³ R⁴ R⁵) may be attached to thetriphenylene ring system at any carbon atom where attachment ispossible. For example, the side chain may be attached to the 2 positionof a triphenylenyl moiety, although attachment to other positions of thetriphenylene ring system is within the scope of the invention.

For antitumor activity the side chain defined by choice of R¹,R²,R³,R⁴,and R⁵ must not preclude in vitro intercalation by the resultingmolecule of formula (I) to DNA. This property is determined usingviscometric methods by the procedure of W. D. Wilson et. al., NucleicAcids Research 4 2697 (1977).

In addition, the log P of the molecule as calculated by the method of C.Hansch and A. Leo in Substituent Constants for Correlation Analysis inChemistry and Biology, John Wiley & Sons, New York, 1979, shouldnormally lie in a range of acceptable values, most conveniently between-2.0 and +2.5.

R¹ is conveniently a straight chain C₁₋₃ alkylene moiety, e.g.,methylene (--CH₂ --).

R² is conveniently hydrogen but C₁₋₆ alkyl, e.g., methyl is also withinthe scope of the invention.

R³ conveniently has the hydroxyl group of the hydroxyalkyl groupattached to an α carbon atom (i.e. the hydroxyl group is 2 carbon atomsremoved from the nitrogen atom of the side chain). For example, R³ maybe hydroxymethyl (--CH₂ OH).

While R⁴ and R⁵ may each be hydrogen, C₁₋₆ alkyl, or hyddroxy C₁₋₆alkyl, conveniently they are alkyl or hydroxyalkyl. Most conveniently atleast one of R⁴ and R⁵ is hydroxyalkyl. When R⁴ and/or R⁵ ishydroxyalkyl the hydroxyl group is conveniently on an α carbon atom, forexample hydroxymethyl (--CH₂ OH).

The preferred side chain to be attached to the triphenylene ring systemis that derived from 2-methyl-2-amino-1,3-propanediol (II) ##STR3##

The triphenylene ring system may optionally bear one or moresubstituents known in the art to be advantageous to the pharmaceutical,pharmacological, or physical properties of a therapeutic agent whenattached to an aromatic nucleus. Suitable substituents include, forexample, halogen (e.g. chloro, bromo), C₁₋₆ alkyl (e.g. methyl, ethyl),C₁₋₆ alkoxy (e.g. methoxy, ethoxy), halo C₁₋₆ alkyl (e.g. 2-chloroethyl,trifluoromethyl) C₁₋₆ alkylthio (e.g. thiomethyl and thioethyl),hydroxyC₁₋₆ alkyl (e.g., 2-hydroxyethyloxy) hydroxy C₁₋₆ alkylthio (e.g.2-hydroxyethylthio), cyano, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphenyl;such substituents will not in general contain or comprise an aromaticmoiety.

Such substituents may be attached to any appropriate position(s) on thetriphenylene ring system.

Esters of compounds of formula (I) are conveniently those derived fromC₁₋₆ alkanoic acids, e.g. acetic acid, propionic acid, n-butyric acidand isobutyric acid. Where the compound of formula (I) contains morethan one hydroxyl group one or more of the hydroxyl groups may beesterified; however it is convenient that all hydroxyl groups areesterified.

Specific compounds within the scope of formula (I) include;

2-Methyl-2-((2-triphenylenylmethyl)amino)-1,3-propanediol,

The compounds of formula (I) may be prepared by any method known in theart for the preparation of compounds of analogous structure. Thus thecompounds of formula (I) may, for example, be prepared by any of themethods defined below.

1. Reductive amination of a compound of formula (III) with a compound offormula (IV): ##STR4## wherein Ar, R¹, R², R³, R⁴ and R⁵ are as definedherein above. The conditions and reagents for such a reaction are wellknown in the art of organic chemistry and any such conditions/reagentsmay be employed. For example, sodium cyanoborohydride (NaBH₃ CN)conveniently comprises the reducing agent, and is used according toprocedures outlined by R. O. Hutchins et. al., Organic Preparations andProcedures International 11 201 (1979).

2. Reduction of a compound of formula (V) also formed by reaction ofcompounds (III) and (IV): wherein Ar, R¹,R²,R³,R⁴, and R⁵ are as definedabove. ##STR5## The reducing agent may conveniently be LiAlH₄, NaBH₄, orhydrogen and a catalyst, or equivalent reagent as outlined by J. March,Advanced Organic Chemistry, 2nd ed., pages 682-683, McGraw Hill, NewYork, 1977. Compound (V) can also be made according to proceduresoutlined by J. March, vide supra page 667.

In turn, a compound of formula (III) (n=0) can be synthesised byreacting the appropriate triphenylene derivative with SnCl₄ and Cl₂CHOCH₃ or equivalent reagents, for example, according to the method A.Rieche et. al., Chem. Ber. 93, 88 (1960).

A compound of formula (III) (n=0) can also be synthesized by reactingthe required triphenylene derivative with other appropriate formylatingreagents/procedures known to the art, for example, as outlined by J.March, vide supra pages 416-420.

Appropriately substituted triphenylene derivatives may be converted tothe corresponding aldehydes (III) (n=0-2) by any method known to theart.

Where the triphenylene ring bears substituents, the appropriate compoundmay in turn be prepared by a variety of methods known in the art oforganic chemistry depending on the nature of the substituent on thering. For example if the substituent(s) is a halogen, the startingmaterials may be prepared by direct treatment of the triphenylenederivative with a halogenating agent (e.g. Cl₂, Br₂, or SO₂ Cl₂) orindirectly by such routes as the Sandmeyer reaction (D. T. Moury, Chem.Rev. 42 213 (1948)). If the substituent(s) is alkyl, the triphenylenederivative may be reacted with the appropriate reagents underFriedel-Crafts reaction conditions (P. Gore, Chem. Rev. 55 229 (1955)).

3. Reacting a compound of formula (VI) wherein R³,R⁴, and R⁵ are definedas above but at least one is H, and L is a leaving group as defined byJ. March, vide supra pages 683 and 895, (e.g., Br, Cl,p-toluenesulfonate, etc.) with a compound of formula (VII). ##STR6##wherein Ar, R¹ and R² are as defined above.

A compound of formula (VII) can be synthesised by the method ofreductive amination described above whereby reacting a compound offormula (III), and R² NH₂ (wherein R² is as defined above), in thepresence of a reducing agent, for example sodium cyanoborohydride, orany other methods described in 2 or which are known to the art.

4. Reacting a compound of formula (VIII), wherein Ar, R¹, and L aredefined

    Ar--R.sup.1 --L                                            (VIII)

as above with a compound of formula (IV) as defined above.

5. Reacting a compound of formula (IX), wherein Ar is defined above##STR7## and X is a halogen or equivalent leaving group with a compoundof formula (IV) as defined above (preferably with any of the hydroxygroup(s) appropriately protected) followed by reduction of the resultingamide with a reducing agent such as, for example, LiAlH₄ or equivalentagent. The reduction may be followed by deprotection if required. Thecompound of formula (IX) may be prepared by any of the widely knownmethods in the art for preparing similar compounds.

There is therefore provided, as a further aspect of the invention, amethod for the preparation of a compound of formula (I) comprising anymethod known for the preparation of analogous compounds, in particular,those methods defined in (1) to (5) hereinabove.

The compounds of this invention have been found to have antitumoractivity. Such activity is evidenced by reduction of tumor cell numberin mammals bearing ascitic tumors and their consequent increase insurvival duration as compared to a control group which is untreated.Antitumor activity is further evidenced by measurable reduction in thesize of solid tumors in animals following treatment of the animal withthe compounds of this invention compared to the tumors of untreatedcontrol tumor-bearing animals. The murine tumor lines against which thecompounds of formula (I) are active include, but is not limited to,lymphocytic leukemia P388/0. Activity has also been demonstrated againstsublines of the P388/0 which are resistant to a number ofchemotherapeutic agents now in clinical use.

(As used herein "cancer" is to be taken as synonymous with "malignanttumor" or more generally "tumor" unless otherwise noted).

As has been described above, the compounds of the present invention areuseful for the treatment of tumors. The invention thus further providesa method for the treatment of tumors in animals, including mammals,which comprises the administration of an effective, non-toxic amount ofthe compound of formula (I), an ester thereof, or an acid addition saltthereof, once, or several times a day orally, parenterally (includingsubcutaneous, intramuscular and intravenous), or applied topically.There is also provided as a further or alternative aspect of theinvention, a compound of formula (I) for use in therapy, for example asan antitumor agent.

The amount of compound of formula (I) required to be effective as anantitumor agent will, of course, vary and is ultimately at thediscretion of the medical or veterinary practitioner treating themammal. The factors to be considered by such a practitioner, e.g., aphysician, include; route of administration and pharmaceuticalformulation; the mammal's body weight, surfacce area, age, and generalcondition; the particular salt or ester to be administered. However, asuitable effective antitumor dose is in the range of about 0.1 to about120 mg/kg bodyweight, preferably in the range of about 1.5 to 50 mg/kg,e.g., 10 to 30 mg/kg. The total daily dose may be given as a singledose, multiple doses, e.g., two to six times p.d., or by intravenousinfusion for any selected duration. For example, the dose range would beabout 5 to 500 mg/kg per day. A typical dose for a 75 kg mammal would beabout 2000 mg per day. If discrete multiple doses are indicated,treatment might typically be 500 mg of a compound of formula (I) given 4times p.d. in the form of a tablet, capsule, liquid (e.g., syrup) orinjection.

The antitumor activity of the compounds of formula (I) resides in thefree base and thus the nature of the acid participating in the acidaddition salts is of minor importance. However, when used in medicine,the salts of the compound of formula (I) should be bothpharmacologically and pharmaceutically acceptable, butnon-pharmaceutically and non-pharmacologically acceptable salts mayconveniently be used to prepare the free active compound orpharmaceutically acceptable salts thereof and are not excluded from thescope of this invention. Such pharmacologically and pharmaceuticallyacceptable salts include, but are not limited to, those prepared fromthe following acids: hydrochloric, hydrobromic, sulfuric, nitric,isethionic, phosphoric, maleic, salicyclic, p-toluenesulfonic, tartaric,lactic, citric, methanesulfonic, lactobionic, formic, malonic,pantothenic, succinic, naphthalene-2-sulfonic and benzenesulfonic.

While it is possible for the active compound (defined herein as compoundof formula (I)) to be administered alone as the raw chemical, it ispreferable to present the active compound as a pharmaceuticalformulation. Formulations of the present invention, for medical use,comprise the active compound together with one or more pharmaceuticallyacceptable carriers thereof and optionally any other therapeuticingredients. The carrier(s) must be pharmaceutically acceptable in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

The present invention therefore further provides a pharmaceuticalformulation comprising a compound of formula (I) or an ester thereof (inthe form of the free base or a pharmaceutically acceptable acid additionsalt) together with a pharmaceutically acceptable carrier.

There is also provided a method for the preparation of pharmaceuticalformulation which comprises bringing into association a compound offormula (I) or an ester thereof and a pharmaceutically accceptablecarrier thereof.

The formulations include those suitable for oral, rectal, or parenteral(including subcutaneous, intramuscular, and intravenous injection)administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into association with a liquidcarrier, a finely divided solid carrier, or both, and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets,or lozenges, each containing a predetermined amount of the activecompound; as a powder or granules; or a suspension in an aqueous liquidor non-aqueous liquid such as a syrup, an elixir, an emulsion, or adraught. The active compound may also be presented as a bolus,electuary, or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine, the active compound in a free-flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, surfactant, or dispersing agent. Moldedtablets may be made by molding in a suitable machine, a mixture of thepowdered active compound with any suitable carrier.

A syrup may be made by adding the active compound to a concentrated,aqueous solution of a sugar for example sucrose to which may also beadded any accessory ingredient. Such accessory ingredient(s) may includeflavorings, an agent to retard crystallization of the sugar or an agentto increase the solubility of any other ingredient, such as a polyhydricalcohol (e.g. glycerol or sorbitol).

Formulations for rectal administration may be presented as a suppositorywith a usual carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient.

In addition to the aforementioned ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders, surfaceactive agents, thickeners, lubricants, preservatives (includingantioxidants) and the like.

The following examples are provided by the way of illustration of thepresent invention and should in no way be construed as a limitationthereof.

GENERAL COMMENTS

All solvents were reagent grade and used without further purificationwith the following exceptions. THF was dried by distillation from Na/Kalloy under N₂ and used immediately. Toluene (PhCH₃) was distilled fromCaH₂ under N₂ and stored over 3Å molecular sieves. Chemicals used werereagent grade and used without purification unless noted. The full nameand address of the suppliers of the reagents and chemicals is given whenfirst cited. After this, an abbreviated name is used.

Preparative HPLC was carried out on a Water's Prep LC/System 500Amachine using two 500 g silica gel (SiO₂) cartridges unless otherwisenoted. Plugs of SiO₂ used for purifications were "flash chromatography"silica gel (E. Merck, silica gel 60, 230-400 mesh). An appropriatevolume sintered glass funnel was filled approximately 3/4 full with theSiO₂ and packed evenly by tapping the outside of the funnel. A piece offilter paper was then placed on top of the SiO₂ and a solution of thematerial to be purified applied evenly to the top. Gentle suctionthrough a filter flask moved the eluting solvent through the plugrapidly. The appropriate size fractions were combined as needed andfurther manipulated.

General procedures are described in detail. Analogous procedures showmelting point (mp), recrystallization solvents, and elemental analyses(all elements analyzing within a difference of ≦0.4% of the expectedvalue). Any changes to the procedure such as solvent, reactiontemperature, reaction time, or workup are noted.

NMR (¹ H,¹³ C), IR, MS data of all new products were consistent with theexpected and proposed structures. The positions assigned to structuralisomers were unequivocally determined by a number of NMR techniques. Allfinal products were dried in a vacuum oven at 20 mm Hg pressure at thetemperature indicated overnight (12-16 h). All temperatures are indegrees Celsius.

EXAMPLE 1 2-Methyl-2-((2-triphenylenylmethyl)amino)-1,3-propanediol,hydrochloride A. 2-Triphenylenecarbaldehyde

A 1 L 3-neck flask fitted with overhead mechanical stirrer, thermometer,condenser, and N₂ line was charged with triphenylene (Aldrich ChemicalCo., Milwaukee, WI, 53201, 30 g, 0.131 mol) and o-dichlorobenzene (150mL). The liquid was warmed until all the large chunks of solid dissolved(80°) and then cooled quickly to give finely divided crystals. Afterfurther cooling with a salt-ice bath to 5°, SnCl₄ (Aldrich, 98%, 58 g,0.223 mol, 26 mL), was added in one portion to the mixture. Notemperature change occurred. The pot temperature was kept below 5°, and1,1-dichloromethylmethylether (Aldrich, 25.6 g, 0.223 mol, 20 mL) wasadded dropwise over 1 h. The resulting suspension was warmed slowly to40° over 2 h and further stirred for 16 h. Considerable HCl gasevolution occurred during the warming and the early part of the reactionat 40°. The reaction mixture was then cooled to 10° and hydrolysed bycareful addition of 1 L of cold H₂ O. After 4 h the layers wereseparated and the organic layer filtered, dried with anhydrous Na₂ SO₄(Mallinckrodt Co., 2nd and Mallinckrodt St., St. Louis, MO, 63147, 100g) and filtered again. The solvent was removed to give a crude yellowoil which was purified by preparative HPLC using PhCH₃ as the elutingsolvent. The fractions containing the aldehyde were combined and thesolvent removed to give an oil which solidified (8.31 g, 25%). Thismaterial was used without further purification. Recrystallization fromCH₂ Cl₂ /CH₃ OH gave pure 2-triphenylenecarbaldehyde mp 160°-161.5°,(C,H).

B. 2-Methyl-2-((2-triphenylenylmethyl)amino)-1,3-propanediolhydrochloride

To a 1 L Erlenmeyer flask was added 2-triphenylenecarbaldehyde 5.13 g,(20 mmol), 2-methyl-2-amino-1,3-propanediol (Aldrich, 2.2 g, 21 mmol),p-toluenesulfonic acid.H₂ O (Eastman Kodak Co., Rochester, NY, 14650,0.1 g, 0.5 mmol), and PhCH₃ (250 mL). The mixture was warmed to refluxfor a few minutes and H₂ O (2-3 mL) was driven off. The resulting goldencolored solution was allowed to cool to RT, diluted with absolute EtOH(250 mL) and stirred overnight. NaBH₃ CN (Aldrich, 95%, 0.63 g, 10 mmol)was added to the reaction. After the NaBH₃ CN dissolved, an indicator(bromocresol green, Eastman, 5 mg) was added. To the ressulting bluesolution was added 5 drops of 1M solution of HCl gas in absolute EtOHevery 15 minutes. After 3 days the indicator turned green then yellowand voluminous white precipitate was present in the flask. To the flaskwas then added 1M gas HCl (10 mL) in absolute EtOH. The reaction wasdiluted to 2 L with absolute ether and stirred for 1 h. The precipitatewas then collected by filtration through a medium porosity glass frittedfunnel and pressed dry. The filter cake was washed thoroughly with 20%HCl (2×250 mL), pressed dry and then washed with CH₂ Cl₂ (4×500 mL),pressed and sucked dry. The crude off-white solid was thenrecrystallized (EtOH/Et₂ O) 3x to give after drying (100°) 3.34 g (43%)of 2-methyl-2-((2-triphenylenylmethyl)amino)-1,3-propanediolhydrochloride.1/2 H₂ O mp 207°-208.5° (dec), (C,H,Cl,N).

Antitumor Screening Results

Methods for evaluating the antitumor activity of these compounds areessentially those used in the Tumor Panel by the DevelopmentalTherapeutics Program, Division of Cancer Treatment, National CancerInstitute, A. Goldin, et al., Methods in Cancer Research, Vol. XVI, p.165, Academic Press (1979). Some modifications, in dose level andschedule have been made to increase the testing efficiency.

EXAMPLE 2 Lymphocytic Leukemia P388/0 Test

CD2-F₁ mice, of the same sex, weighing within a 3 g range surrounding 20g, are used for this test. Control and test animals are injectedintraperitoneally with a suspension of ˜10⁶ viable P388/0 tumor cells onday 0. In each test several dose levels which bracket the LD₂₀ for thecompound are evaluated; each dose level group contains 6 animals. Thetest compounds are prepared either in physiologic saline containing0.05% Tween 80 or distilled water containing 5% dextrose and areadministered intraperitoneally on days 1,5, and 9 relative to tumorimplant. Doses are on a mg/kg basis according to individual animals'body weights. The day of death for each animal is recorded, the medianidentified for each group and the ratios of median survival time fortreated (T)/control (C) groups are calculated. The criterion foractivity is T/C×100≧120%. The results of P388/0 testing are summarizedin Table I below.

                  TABLE I                                                         ______________________________________                                        P388/0 Testing on Compound of Example 1                                                         Median             No Cells                                 Dose    30 Day    Day of             Surviving                                (mg/kg) Survivors Death     T/C × 100%                                                                       Therapy                                  ______________________________________                                        125     0/6       17.5      +175     Toxic                                    84      0/6       20.0      +200     1.9 × 10.sup.5                     56      0/6       17.0      +170     2.7 × 10.sup.7                     Untreated                                                                             0/6       10        --       --                                       Controls                                                                      ______________________________________                                    

Example 3 Formulation Examples

    ______________________________________                                        A. TABLET                                                                     ______________________________________                                        Compound of Formula I   500.0  mg                                             Pregelatinized Corn Starch                                                                            60.0   mg                                             Sodium Starch Glycolate 36.0   mg                                             Magnesium Stearate      4.0    mg                                             ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, pregelatinized corn starch and sodium starchglycolate. The powders are wetted with purified water to form granules.The granules are dried and mixed with the magnesium stearate. Theformulation is then compressed into tablets weighing approximately 600mg each.

    ______________________________________                                        B. TABLET                                                                     ______________________________________                                        Compound of formula (I) 500.0  mg                                             Corn Starch             70.0   mg                                             Lactose                 83.8   mg                                             Magnesium Stearate      4.2    mg                                             Polyvinylpyrrolidone    14.0   mg                                             Stearic Acid            28.0   mg                                             ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, corn starch and lactose. The powders are wettedwith a solution of polyvinylpyrrolidone dissolved in purified water anddenatured alcohol to form granules. The granules are dried and mixedwith the powdered stearic acid and magnesium stearate. The formulationis then compressed into tablets weighing approximately 700 mg each.

    ______________________________________                                        C. CAPSULES                                                                   ______________________________________                                        Compound of formula (I) 500.0  mg                                             Corn Starch             50.0   mg                                             Magnesium Stearate      3.0    mg                                             ______________________________________                                    

The finely divided compound of formula (I) is mixed with powdered cornstarch and wetted with denatured alcohol to densify the powder. Thedried powder is mixed with stearic acid and filled into hard-shellgelatin capsules.

    ______________________________________                                        D. SYRUP                                                                      ______________________________________                                        Compound of formula (I)                                                                              250.0   mg                                             Ethanol                250.0   mg                                             Glycerin               500.0   mg                                             Sucrose                3,500.0 mg                                             Flavoring Agent        q.s.                                                   Coloring Agent         q.s.                                                   Preserving Agent       0.1%                                                   Purified Water q.s. to 5.0     ml                                             ______________________________________                                    

The compound of formula (I) is dissolved in the ethanol, glycerin, and aportion of the purified water. The sucrose and preserving agent aredissolved in another portion of hot purified water, and then thecoloring agent is added and dissolved. The two solutions are mixed andcooled before the flavoring agent is added. Purified water is added tofinal volume. The resulting syrup is throughly mixed.

    ______________________________________                                        E. IV INJECTION                                                               ______________________________________                                        Compound of formula (I)                                                                         5.0 mg                                                      Glycerin          q.s. for isotonicity                                        Preservative      0.1%                                                        Hydrochloric Acid or                                                                            as needed for                                               Sodium Hydroxide  pH adjustment                                               Water for Injection                                                                             q.s. to 1 ml                                                ______________________________________                                    

The compound of formula (I) and preservative is added to the glycerinand a portion of the water for injection. The pH is adjusted withhydrochloric acid or sodium hydroxide. Water for injection is added tofinal volume and solution is complete after thorough mixing. Thesolution is sterilized by filtration through a 0.22 micrometer membranefilter and aseptically filled into sterile 10 ml ampules or vials.

What is claimed is:
 1. A compound of formula (I) ##STR8## wherein Ar isa triphenylene or a triphenylene ring system substituted with halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, halo C₁₋₆ alkyl, C₁₋₆ alkylthio, hydroxy C₁₋₆alkyl, hydroxy C₁₋₆ alkylthio, cyano, C₁₋₆ alkylsulphinyl or C₁₋₆alkylsulphenyl; R¹ is a C₁₋₃ alkylene moiety, R² is hydrogen or a C₁₋₆alkyl group; R³ is a hydroxxy C₁₋₆ alkyl group; and R⁴ and R⁵ are thesame or different and are hydrogen, C₁₋₆ alkyl groups or hydroxy C₁₋₆alkyl group, or a C₁₋₆ alkyl carboxylic acid ester thereof.
 2. Acompound of claim 1 which is2-methyl-2-((2-triphenylenylmethyl)amino)-1,3-propanediol or a C₁₋₆alkylcarboxylic acid ester derived therefrom or a pharmaceuticallyacceptable acid addition salt thereof.
 3. The hydrochloric acid salt ofthe compound of claim
 2. 4. The hydrochloric acid salt of a compound ofclaim
 1. 5. The citric acid salt of a compound of claim
 1. 6. The aceticsalt of a compound of claim
 1. 7. The methanesulfonic acid salt of acompound of claim
 1. 8.2-Methyl-2-((2-triphenylenylmethyl)amino)-1,3-propanediol.
 9. Apharmaceutically acceptable acid addition salt of2-methyl-2-((2-triphenylenylmethyl)amino)-1,3-propanediol.